Our most powerful antimicrobials are rapidly becoming non-protective. From common Staph infection to tuberculosis, the rapid emergence of drug-resistant microbes threatens to roll back the clock on disease control to an era when everyday infections were deadly. The fundamental problem with our current therapies is that pathogens are dynamic?they mutate and transmit?while our therapies are static, neither mutating nor transmitting. This mismatch necessarily selects for drug-resistant escape variants, which arise far quicker than current platforms can identify and develop new antimicrobials. Faced with dynamic pathogens, I propose a radical shift in treatment strategy toward engineering dynamic, evolvable therapies. For viruses, these dynamic therapies are based on engineered molecular parasites that can only replicate using the molecular machinery of the virus (i.e., they ?piggyback?). In the case of HIV, these molecular parasites are pared-down HIV vectors where the essential protein products have been ablated, forcing the vectors to intracellularly compete for viral replication and packaging resources, thereby generating Therapeutic Interfering Particles (TIPs) from HIV-infected cells. By starving HIV of its own essential elements, TIPs act as therapy, reducing viral loads in the patient. The fundamental departure from traditional therapies is that TIPs harness the inherent biology of the pathogen, replicating with equal speed and with the same evolutionary adaptive potential as the pathogen. TIPs are under strong evolutionary selection to maintain their parasitic relationship with the pathogen and natural selection pushes the molecular parasite to co-evolve and keep pace with the pathogen (i.e., establishing a co-evolutionary ?arms race? between therapy and pathogen). This proposal will develop a new set of technologies to propel the concept of co-evolving anti-pathogen molecular parasites. Studying evolution represents an entirely new direction for my lab. To test if co-evolution between pathogen and molecular parasite is robust and therapeutic, we will examine TIP-based therapy against the rapidly evolving HIV-1 virus. First, we will develop a novel cell-culture viral bioreactor (a ?Viroreactor?) to track HIV-TIP co-evolution at near-physiological scales. Conventional cell-culture approaches cannot capture realistic rates of viral evolution since these approaches create evolutionary ?bottlenecks? and ?saw-tooth-like? profiles of virus that are artifacts of serial passage in culture. In parallel, I will also develop a new mathematical theory for co-evolution of molecular-parasite therapies to predict the co-evolutionary dynamics between HIV and TIP. This theory will enable design of efficient TIPs and predict design requirements for the Viro-reactor, such as experiment size and duration. Finally, we will test the coevolutionary potential and therapeutic efficacy/safety of novel TIP interventions in an established non-human primate model of HIV infection. Collectively, these assays will test a radically new therapeutic concept, with the aim of transforming infectious disease control from static to dynamic, evolvable interventions.